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Review of the Grazoprevir Patent Landscape:A scoping report

2015

JULY 2015

UNITAID SecretariatWorld Health OrganizationAvenue Appia 20CH-1211 Geneva 27SwitzerlandT +41 22 791 55 03F +41 22 791 48 [email protected]

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iiiTechnical Report

CONTENTSAbbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ivI. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1II. METHODOLOGY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2III. BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Hepatitis C virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Grazoprevir. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

IV. OVERVIEW OF GRAZOPREVIR PATENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5V. ANALYSIS OF GRAZOPREVIR PATENTS/APPLICATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . 7ANNEX 1. Grazoprevir patent situation in countries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21ANNEX 2. Process chemistry extracted from grazoprevir patents/applications . . . . . . . . . . . 27

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Review of the Grazoprevir Patent Landscape

AbbreviationsAPI active pharmaceutical ingredient

AUC area under the (plasma concentration/time) curve

DAA direct-acting antiviral

HCV hepatitis C virus

HIV human immunodeficiency virus

PCT Patent Cooperation Treaty

RNA ribonucleic acid

1Technical Report

1. INTRODUCTIONHepatitis C virus (HCV) is a major global health problem. With 80−150 million people worldwide chroni-cally infected with the virus, the prevalence of HCV is higher than that of the human immunodeficiency virus (HIV). It is estimated that, worldwide, 4−5 million people are coinfected with HIV and HCV. Each year, 500 000−700 000 people die of HCV-related liver disease, and evidence indicates that the HCV burden is increasing.1,2 While the HCV epidemic is global in scope, the HCV burden varies considerably between countries.

The virus has six primary genotypes. Genotypes 1 and 3 are the most prevalent, accounting respectively for 46% and 30% of HCV cases worldwide. Together, genotypes 2, 4 and 6 represent around 23% of HCV cases, while genotype 5 accounts for less than 1%.3

Efforts to treat HCV have historically been hampered by suboptimal and inadequate treatments. However, the development of direct-acting antivirals (DAAs) has dramatically improved HCV treatment prospects and has altered the standard of care. Several new DAAs that do not require pegylated interferon were launched in late 2013 and in 2014, and a number of other DAAs are in development.

These DAAs generate cure rates that approach or exceed 90%. Some combination regimens may have pan-genotypic efficacy, which would simplify treatment and monitoring.

UNITAID’s Hepatitis C Medicines Technology and Market Landscape, published in February 2015, identi-fied Merck’s investigational compound MK-5172 – grazoprevir – as being of interest. The combination grazoprevir/elbasvir has breakthrough therapy designation in the United States for treatment of certain patients with chronic HCV infection.

In view of grazoprevir’s potential role in future treatment, this report explores the patent landscape of grazoprevir.

1 Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2095−128.2 GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age–sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;385(117−71).3 Messina JP, Humphreys I, Flaxman A, Brown A, Cooke GS, Pybus OG et al. Global distribution and prevalence of hepatitis C virus genotypes. Hepatology. 2014;61(1):77−87.

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II. METHODOLOGYRelevant patents and patent applications were identified by searching patent and non-patent databases, namely: PatBase, TotalPatent, SciFinder and Google patent. Searches were carried out using keywords, semantic searches and structure searches.

For each of the most relevant patents or applications, the equivalents were identified (INPADOC family) and the legal status of each of the equivalents was checked on the websites of the relevant patent offices. The countries listed in Annex 1 represent those for which INPADOC data is available.

Data for Thailand and Viet Nam were checked by local patent attorneys at the local patent office. In Paki-stan, the local patent office provided a search for equivalents to help prepare this report.

The searches were carried out in January 2015. The analysis of the identified patents and patent applica-tions was undertaken on the basis of the European patent/application unless otherwise indicated.

Caveat: It is important to note that the patent status of a given product in a given country may change and that data may therefore become outdated. It is advisable always to check with the relevant national or regional patent office for the most up-to-date information on the status of a given patent or patent application.

This report was prepared by Andrew Brown and Amel Garbi (Pharmathen), with input from Karin Tim-mermans (UNITAID). The patent searches were conducted by Amel Garbi (Pharmathen).

The following reviewers provided valuable input, comments and suggestions on all or part of a draft version of this report: Peter Beyer, Esteban Burrone, Yao Cheng, Ellen ‘t Hoen, Yuanqiong Hu and Leena Menghaney.

3Technical Report

III. BACKGROUND

Hepatitis C virusThe hepatitis C virus is a small (55−65 nm), enveloped, positive-sense single-stranded RNA virus of the Flaviviridae family. The virus consists of three structural proteins (core, E1 and E2), the ion channel protein p7, and six non-structural (NS) proteins (NS2, NS3, NS4A, NS4B, NS5A and NS5B) (see Figure 1). Each of these proteins plays a role in HCV entry, infection, replication or maturation and is therefore a potential target for medicines.

Figure 1. Hepatitis C virus RNA

Source: Graham Colm.

DAAs block viral production by directly inhibiting one or more steps of the HCV replication cycle. DAAs can be divided into categories – notably NS3/NS4A serine protease inhibitors, NS5A complex inhibitors and NS5B RNA polymerase inhibitors (both nucleoside and non-nucleoside).

Grazoprevir is an NS3/NS4A protease inhibitor that is currently in phase III clinical trials.

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In April 2015, Merck announced that the United States Food and Drug Administration (FDA) had granted breakthrough therapy designations to grazoprevir/elbasvir for treatment of certain patients with chronic HCV infection (genotypes 1 and 4).4 Breakthrough therapy designation is intended to expedite the devel-opment and review of a candidate that is planned for use, alone or in combination, to treat a serious or life-threatening disease or condition when preliminary clinical evidence indicates that the drug may dem-onstrate substantial improvement over existing therapies on one or more clinically significant endpoints.

GrazoprevirGrazoprevir (MK-5172) is a novel P2-P4 quinoxaline macrocyclic HCV NS3/4A protease inhibitor. The structure of grazoprevir is shown in Figure 2.

Figure 2. Structure of grazoprevir

Chemical name: (1aR,5S,8S,10R,22aR)-5-tert-butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide.

Molecular formula: C38H50N6O9S

Molecular weight: 766.9034 g/mol

CAS registry numbers:

1350462-55-3 for the hydrate form; and

1350514-68-9 for the anhydrous form.

4 Grazoprevir/Elbasvir, Merck’s Investigational Chronic Hepatitis C Therapy, Granted FDA Breakthrough Therapy Designations; New Phase 2 and 3 Data in Multiple HCV Patient Types to be Presented at The International Liver CongressTM 2015. Business Wire, 8 April 2015.

5Technical Report

IV. OVERVIEW OF GRAZOPREVIR PATENTSNine patents and/or patent applications related to grazoprevir (MK-5172) have been identified as appear-ing to be the most relevant. These nine patents/applications, and a divisional patent/application, include the patent/application covering the compound per se, as well as processes for preparing it and formula-tions and combinations that include it.

Patent 1 and patent 2 are the main patents; they cover the compound grazoprevir and would likely block the production, import, marketing and use of generic versions of grazoprevir in countries where one or both patents are in force.

Patents 3 to 9 can also hamper the production, import, marketing and use of generic versions of grazo-previr in countries where they are granted, but they are not as absolute a barrier to generic production, import and use as patents 1 and 2.

Patents 3, 7 and 8 relate to combinations that include grazoprevir. Patent 3 claims the combination grazo-previr/elbasvir. Patent 7 claims combinations of grazoprevir with several other HCV medicines, but not the combination with elbasvir. Patent 8 claims combinations of ombitasvir with other HCV medicines, includ-ing the combination of ombitasvir with grazoprevir for use with or without ribavirin.

Patent 4 covers certain crystalline forms of grazoprevir.

Patents 5, 6 and 9 relate to synthetic routes that can be used to produce grazoprevir.

A brief overview of the nine most relevant patents and/or applications can be found in Table 1. More extensive information is provided in section V and Annex 1.

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Table 1. Overview of key patents on grazoprevir

Application/patent number Applicants Filing date Comments

1. EP2086982AWO2008057209A

Merck (USA)MSD Italia (IT)

23.10.2007Broad compound patent (Markush formula). Likely to block generic market entry where it is in force.

2. EP2310095BWO2010011566A


17.07.2009Basic compound patent; claims the API. Likely to block generic market entry where it is in force.

EP2540349BEP2540350B

DivisionalDivisional

Divisionals to the basic compound patent (patent 2).

3. EP2621501AWO2012050850A

Merck (USA) 28.09.2011Combination grazoprevir/ elbasvir and its use.

4. EP2744507AWO2013028465A

Merck (USA & UK)

16.08.2012Several different crystal forms of grazoprevir.

5. EP2744331AWO2013028471A

Merck (USA & UK)

16.08.2012Intermediates and processes for the production of grazoprevir.

6. EP2744336AWO2013028470A

Merck (USA & UK)

16.08.2012Intermediates and processes for the production of grazoprevir.

7. EP2773342AWO2013066753A


26.10.2012Combination of grazoprevir and certain other HCV inhibitors (but not grazoprevir/elbasvir).

8. EP2797594AWO2013101552A

AbbVie (USA) 18.12.2012Combination of ombitasvir with certain other HCV inhibitors, including ombitasvir/ grazoprevir.

9. EP2802595AWO2013106631A

AbbVie (USA) 11.01.2013Intermediates and processes for the production of grazoprevir.

Patent 1 was published before the main grazoprevir compound patent – patent 2 – was filed. Therefore, patent 1 can be cited for novelty and inventive step against the main compound patent (patent 2). On the basis of evidence submitted by the applicant (in the application for patent 2), showing a benefit of grazo-previr over the compounds of patent 1, compound patent 2 falls within the scope of the earlier published patent 1. In other words, patent 1 would be relevant prior art for patent 2.

Patents 5, 6 and 9 describe synthetic routes that can be used to produce grazoprevir (the API). These routes can be used in countries where the respective patents are not in force or after they expire (which would be after the expiry of patents 1 and 2). Patents 1 and 2 also describe synthetic routes that can be used to make grazoprevir. As these synthetic routes are disclosed but not claimed, the chemical processes to synthesize grazoprevir described in patents 1 and 2 could be used to manufacture grazoprevir before patents 1 and 2 expire.

7Technical Report

V. ANALYSIS OF GRAZOPREVIR PATENTS/APPLICATIONS

Patent 1 Title: HCV NS3 protease inhibitors.

WO2008057209 (Merck (US) and MSD Italia (IT), filed 23.10.2007); EP2086982A

SummaryThis is a broad compound patent that claims compounds of Markush formula (I), including grazoprevir.

This patent would likely block generic market entry in the countries where it is in force.

DescriptionGrazoprevir (MK-5172), Merck’s investigational NS3/4A protease inhibitor, has a chemical structure that is very close to the claimed compounds (I) and thus this application is considered as closest prior art.

The compound of example 118 is structurally the closest compound to grazoprevir. The difference between the two compounds is the presence of a cyclopentyl group for compound 118 instead of a cyclopropyl group for grazoprevir (see the chemical structures below).

compound 118 grazoprevir

Synthetic schemes disclosed in the present application and procedures detailed in the illustrative examples can be applied to the preparation of grazoprevir.

The compounds disclosed and claimed in this patent/application are of Markush formula (I) wherein all substituents are defined in the description and claims.

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formula (I)

This application relates to macrocyclic compounds (I) and/or to pharmaceutically acceptable salts or hydrates thereof that are useful as inhibitors of the HCV NS3 protease in the prevention or treatment of one or more of the symptoms of HCV infection, either as compounds or as pharmaceutical composition ingredients.

As pharmaceutical composition ingredients, these compounds, their salts and hydrates may be the pri-mary active therapeutic agent and, when appropriate, may be combined with other therapeutic agents, including but not limited to other HCV antivirals, anti-infectives and immunomodulators.

The application also claims pharmaceutical compositions comprising an effective amount of the com-pound according to any one of claims 1−15 and a pharmaceutically acceptable carrier and its use.

The application discloses, but does not claim, processes for the preparation of compounds claimed and their key intermediates. By using appropriate intermediates (A1, B27 and C17), the compound of example 118 was prepared according to the procedures of example 94 in the patent application (see Annex 2).

Observations Patent 1 was published before patent 2 and is citable for novelty and inventive step against the main com-pound patent 2 (i.e. patent 1 would be relevant prior art for patent 2).

In countries where compound patent 2 has not been filed or has not been granted, patent 1 will likely constrain the production, import and use of generic versions of grazoprevir (when granted).

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Technical Report

Patent 2 Title: Macrocyclic quinoxaline compounds as HCV NS3 protease inhibitors.

WO2010011566 (Merck & Inst Di Ricerche Di Biologia Molecolare P. Angeletti, filed 17.07.2009); EP2310095B

SummaryThis is the basic compound patent covering grazoprevir. The patent claims grazoprevir (the API) as well as pharmaceutical compositions comprising it, its use and its combination with other HCV agents.

This patent would likely block generic market entry in the countries where it is in force.

DescriptionThis patent claims a macrocyclic quinoxaline compound – grazoprevir – and pharmaceutically acceptable salts thereof, as well as its use as an inhibitor of HCV NS3 protease and its use in treating or preventing HCV infections.

The patent also claims compositions comprising an effective amount of grazoprevir and methods of use, its administration and form/route of administration, and its use in combination treatments involving one or more additional therapeutic agents.

Grazoprevir is a selection compound from compounds disclosed and claimed in PCT application WO2008057209 (patent 1). In patent 2, the patentee has put forward advantageous properties of grazo-previr over the compounds of patent 1 (notably the compounds of examples 110 and 118 of patent 1) in order to overcome the inventive step concerns raised in the EPO prosecution and to obtain the grant of the patent.

Grazoprevir was compared to the compounds of examples 110 and 118 of patent 1. The results of this com-parison, as provided by the applicant, are given in Table 1 and Table 2 below; they show the advantage of grazoprevir over the compounds of patent 1.

Grazoprevir, when compared to the compound of example 110 of patent 1, showed advantageous proper-ties for its formulation and administration. This is due mainly to the lack of salt disproportionation which enabled enhanced dissolution in water. The patentee states that the lack of this behaviour provides an unexpected advantage in its formulation for pharmaceutical administration and results in improved phar-macokinetic properties (see plasma AUC and liver exposure for rat and dog) as reported in Table 1.

Additionally, compared to example 110 of patent 1, grazoprevir showed:

■■ low in-vivo covalent binding; and

■■ high plasma and liver exposure.

Grazoprevir showed undetectable binding to plasma proteins following oral administration of a single 20 mg/kg dose to rats. Under the same conditions, the compounds of examples 96, 103, 108 and 118 of patent 1 showed detectable binding to rat liver proteins.

The resistance profile of grazoprevir, when compared with the compound of example 118 of patent 1, showed an improved enzyme affinity (Ki) against different mutant enzymes that are known to confer resistance to HCV NS3 protease inhibitors, as shown in Table 2.

Table 3 below provides additional in-vivo covalent binding data.

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Table 1. Comparison of grazoprevir with compounds of WO2008057209 (patent 1)

Ki: Inhibition constant; reference to < 0.016 nM indicates that the observed activity is less than 0.016 nM, the exact amount less than 0.016 nM was not determined by the assay.

EC50: Effective concentration achieving 50% viral replication suppression.

Gt: Genotype.

AUC: Area under the plasma concentration/time curve.

LOQ: Limit of quantitation (3 pmol/mg).

BLQ: Below limit of quantitation.

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Technical Report

Table 2. Ki values1 vs. 1bmutant enzyme (nM)

Table 3.

ObservationsPatent 2 also discloses, without claiming them, processes for making grazoprevir, including processes for making the key intermediates (see Annex 2). These processes may represent opportunities to produce grazoprevir while avoiding the later patented processes (though the latter may be more efficient).

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PATENT 2 - DIVISIONALSAt the European Patent Office, two divisional patent applications have been filed (EP2540349 and EP2540350).

PATENT 2bTitle: Pharmaceutical compositions comprising a macrocyclic quinoxaline compound which is an HCV NS3 protease inhibitor.

EP2540349B (divisional to EP-B-2310095 (patent 2)).

DescriptionThis patent, divisional to EP’095 (patent 2), claims a pharmaceutical composition that comprises grazo-previr or a pharmaceutically acceptable salt thereof (more specifically the potassium salt) and a pharma-ceutically acceptable carrier. The said composition is in solid form and is suitable for oral administration (e.g. capsule or tablet).

ObservationsIt is likely that the ‘349 patent (patent 2b) would constrain generic market entry in the countries where it is in force.

PATENT 2cTitle: Combinations of a macrocyclic quinoxaline compound which is an HCV NS3 protease inhibitor with other HCV agents.

EP2540350B (divisional to EP-B-2310095 (patent 2)).

DescriptionThis patent is another divisional patent to EP’095 (patent 2). This divisional claims the combination of grazoprevir or a pharmaceutically acceptable salt thereof (more specifically the potassium salt) and one or more additional therapeutic agents.

This patent claims, in a dependent claim, the specific combination: grazoprevir + pegylated interferon-α + ribavirin.

ObservationsWhere granted, the ‘350 patent (patent 2c) would likely constrain generic market entry of formulations containing grazoprevir plus certain other active ingredients.

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Technical Report

PATENT 3 Title: Polycyclic heterocycle derivatives and methods of use thereof for the treatment of viral diseases.

WO2012050850 (Merck Sharp & Dohme, filed 28.09.2011); EP2621501A

SummaryThis application claims the combination grazoprevir/elbasvir. The combination may further comprise a third therapeutic agent selected from an HCV protease inhibitor, an interferon and an HCV polymerase inhibitor.

DescriptionThe PCT application claims compositions comprising a polycyclic heterocycle compound selected from 14 compounds in Table 1 of the patent application (elbasvir is compound 8) or a pharmaceutically accept-able salt thereof, together with an additional therapeutic agent that is selected from compounds F1−F28 (grazoprevir is compound F5) or a pharmaceutically acceptable salt thereof and a pharmaceutically ac-ceptable carrier, with the said composition being effective in treating HCV infection. The application also claims the pharmaceutical composition described above in combination with a second additional thera-peutic agent (pegylated interferon, ribavirin). Finally, the use of the compositions for inhibiting HCV NS5A activity or for preventing and/or treating infection by HCV is claimed.

In the European phase, the claims were found to be novel but not inventive, in view of WO2010011566A (patent 2) or US20080299075A. Additionally, in view of the number of alternative compound combina-tions falling within the scope of the claims as originally filed, the European examiner expressed doubts that all of them possess the type and level of activity claimed; experimental evidence was provided only for the specific combination of compound 2 of Table 1 + F5/F7. The other combinations have been tested neither for their activity nor for synergism.

To overcome the objections of the European examiner, the applicants have submitted amendments (08.10.2014), limiting the scope of the claims. The revised European application provides a composition for the treatment of HCV which comprises one of the compounds of Table 1 + F5/F7.

The compounds of Table 1 (after amendment):

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First additional therapeutic agents (after amendment):

ObservationsThis application is under examination in several countries (see Annex 1). As a result of the European ex-aminer’s observations, the applicants have restricted the scope of the claims of the European application and have provided experimental evidence for the specific combination of compound 2 of Table 1 (elbasvir) with F5 (grazoprevir) or F7. The other combinations have been tested neither for their activity nor for their synergism in any data submitted by the patentee so far.

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Technical Report

PATENT 4Title: Crystal forms of a HCV protease inhibitor.


SummaryThis application claims certain crystalline forms of grazoprevir. It also claims a crystalline sodium salt and a crystalline potassium salt of grazoprevir.

DescriptionThis application discloses and claims six different crystalline hydrate forms of grazoprevir. They are char-acterized by given 2Θ values of the X-ray powder diffraction pattern obtained using copper Kα radiation or by given peaks (ppm) of the solid-state carbon-13 CPMAS NMR. The application identifies hydrate III as being the most stable hydrate form.

The application also discloses and claims a crystalline sodium salt of grazoprevir and a crystalline potas-sium salt characterized by given X-ray powder diffraction patterns obtained using copper Kα radiation.

Another embodiment of the invention is directed to a method of making hydrate III from crude grazoprevir (hydrate-II) using acetone/water and drying.

Finally, the application also claims a pharmaceutical composition comprising an effective amount of the claimed form of grazoprevir with or without a second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators and anti-infective agents.

Observations The application is under examination by the European Patent Office:

■■ The claimed sodium salt and hydrate forms are not disclosed in prior art.

■■ The claimed potassium salt is disclosed in the basic API patent WO2010011566 (patent 2).

■■ According to the European examiner, the applicant has to show that the claimed crystalline sodium salt and hydrates have an unexpected effect (such as stability, bio-availability etc.) over WO’566 (patent 2) in order to be considered inventive.

Provided that generic manufacturers use a different form of grazoprevir, this patent will not constrain generic market entry.

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PATENT 5Title: Methods and intermediates for preparing macrolactams.

WO2013/028471 (Merck Sharp & Dohme, filed 16.08.2012); EP2744331A

SummaryThis application claims intermediates and processes for the preparation of grazoprevir.

DescriptionThis application discloses and claims intermediates and processes for the preparation of macrolactam compounds that are able to inhibit HCV NS3 protease activity. An example described in the application is grazoprevir (compound A). The application also discloses and claims processes for the preparation of these intermediates (see Annex 2).

ObservationsThe application is under examination by the European Patent Office and the United States Patent and Trademark Office.

According to the European patent examiner, all compounds and processes claimed are novel. Howev-er, while claims 1, 8 and 9 do involve an inventive step, claims 2−7 lack an inventive step vis-à-vis WO2010011566 (patent 2) and in view of WO2008057209 (patent 1).

Provided that API suppliers manufacture grazoprevir by different processes and using different intermedi-ates, this patent would not constrain generic market entry.

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Technical Report

PATENT 6Title: Process and intermediates for preparing macrolactams.


SummaryThis application claims intermediates and processes for the preparation of grazoprevir.

DescriptionThis application discloses and claims compounds that are useful as intermediates in the preparation of macrolactams – in particular macrolactam compounds inhibiting HCV NS3 protease activity and, more particularly, grazoprevir. The application also discloses and claims processes for the preparation of these intermediates, as well as processes for the preparation of the macrolactams (see Annex 2).

ObservationsThe application is under examination; according to the European patent examiner:

■■ Claims 1, 4 and 5 lack novelty as being anticipated by WO2010011566 (patent 2).

■■ Claims 1−6 and 13 lack an inventive step as being obvious over WO2010011566 (patent 2) in combination with other prior art, as detailed in the European search report.

■■ Claims 7−10 are both novel and inventive.

Provided that API suppliers manufacture grazoprevir by different processes and using different intermedi-ates, this patent would not constrain generic market entry.

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PATENT 7Title: Compositions useful for the treatment of viral diseases.

WO2013066753 (Merck Sharp & Dohme and Instituto di Ricerche di Biologia Molecolare P. Angeletti, filed 26.10.2012); EP277342A

SummaryThis application concerns the combination of grazoprevir with another HCV inhibitor other than elbasvir and other compounds listed in the disclaimer.

DescriptionThis application claims compositions comprising inhibitors of HCV protease and one or more additional therapeutically effective agents – effective combinations for the treatment of HCV infection and inhibition of HCV viral replication.

The claimed pharmaceutical composition comprises: (i) a pharmaceutically acceptable carrier; (ii) a com-pound selected from Table 1 (grazoprevir is compound 5), or a pharmaceutically acceptable salt thereof; and (iii) one or more primary additional therapeutic agents, or a pharmaceutically acceptable salt thereof selected from HCV protease inhibitors, HCV polymerase inhibitors, HCV NS4A inhibitors and HCV NS5A inhibitors. The claim has a disclaimer – a list of compounds which cannot be primary additional therapeu-tic agents; elbasvir, compound 8, is one of them. Thus, this application does not pertain to the combina-tion of grazoprevir with elbasvir.

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Technical Report

PATENT 8Title: Methods for treating HCV.

WO2013101552 (AbbVie, filed 18.12.2012); EP2797594A

SummaryThis application claims combinations of ombitasvir with another anti-HCV agent, including the combina-tion of ombitasvir with grazoprevir. Each treatment regimen claimed is interferon-free, with or without administering ribavirin.

DescriptionThis application claims combinations of Compound I (ombitasvir), an HCV NS5A inhibitor marketed by AbbVie and described, for example, in US 2010/0317568 with another anti-HCV agent.

The application contains a table that lists 80 non-limiting examples of treatment regimens claimed in the patent application. In each treatment regimen, Compound I (ombitasvir) or a pharmaceutically acceptable salt thereof, and the other anti-HCV agent, are administered daily to an HCV patient. Example 49 refers to the combination of ombitasvir with grazoprevir.

Each claimed treatment regimen claimed is interferon-free, with or without ribavirin.

ObservationsThis application is under examination by the European Patent Office.

This patent application attempts to claim any therapy that uses ombitasvir in combination with other anti-HCV medicines (including grazoprevir) as defined in the patent filing but wherein interferon is not used.

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PATENT 9Title: Processes for making HCV protease inhibitors.

WO2013106631 (AbbVie, filed 11.01.2013); EP2802595A

SummaryThis application claims intermediates and processes for the preparation of HCV protease inhibitors, includ-ing grazoprevir.

DescriptionThis application discloses and claims processes for making HCV protease inhibitors, most of them contain-ing the moiety shown below. These processes permit the incorporation of this moiety, or an equivalent one, into precursors of HCV protease inhibitors.

ObservationsThe application is under examination in several countries (see Annex 1). The European search report is not yet available and no amendments have been filed as yet. To date, only the written opinion of the Inter-national Searching Authority (ISA) has been published, considering the subject matter of claims 1−15 to be novel over the prior art and involving an inventive step.

Provided that the API suppliers manufacture grazoprevir using intermediates that are different from the claimed ones, this patent would not constrain generic market entry.

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ANNEX 1. Grazoprevir patent situation in countries

Technical Report

ANNEX 1. Grazoprevir patent situation in countries The INPADOC patent family members for each of the nine patents/applications are listed in the tables below.

Anticipated expiry dates of patents 1 and 2 have been provided. Differences between countries are due to differences in patent term or because the patent application was filed – on a different date – directly at the concerned office (instead of through the PCT route). The indicated expiry dates therefore must be checked in countries that offer patent term extension/restoration (such as European Union countries, Japan and the USA). If grazoprevir is approved for use, it is likely that the innovator will apply for patent term extension/restoration.

Patent 1 Patent 2 Patent 3 Patent 4WO2008057209A1PCT/US2007/022460

WO2010011566A1PCT/US2009/050915

WO2012050850APCT/US2011/053562

WO2013028465APCT/US2012/051168

Applicants Merck & Co (USA)MSD Italia (IT)

Merck & Co (USA)MSD Italia (IT)

Merck Sharp & Dohme (USA)

Merck Sharp & Dohme (USA & UK)

Filing date 23.10.2007 17.07.2009 28.09.2011 16.08.2012

Title HCV NS3 protease inhibitors.

Macrocyclic quinoxaline compounds as HCV NS3 protease inhibitors.

Polycyclic heterocycle derivatives and methods of use thereof for the treatment of viral diseases.

Crystal forms of a HCV protease inhibitor.

Subject matter Broad compound patent – likely constraining for generic medicines where granted.

Basic compound patent – likely constraining for generic medicines where granted.

Grazoprevir/elbasvir combination with or without a third therapeutic agent.

Six different crystalline hydrate forms of grazoprevir.Process for making hydrate-III from hydrate-II.

Priority data US 60/854,912 – 27.10.2006US 60/997,434 – 03.10.2007

US 61/135,559 – 22.07.2008

US 61/387,825 – 29.09.2010 US 61/525,462 – 19.08.2011US 61/533,439 – 12.09.2011US 61/533,915 – 13.09.2011US 61/539,540 – 27.09.2011

African Regional Intellectual Property Organization*

Argentina Appl. N°: 2009P102779Publ. N°: 072588A1Status not available.

Australia 2007318165BGrantedExpiry: 23.10.2027

2009274190B2GrantedExpiry: 17.07.2029

2011314170A1Under examination


Brazil PI0718161AUnder examination

Canada 2667031CGrantedExpiry: 23.10.2027

2731177CGrantedExpiry: 17.07.2029


2844386AUnder examination

China Appl. N°: 200780048666Publ. N°: 101611039AUnder examination

Appl. N°: 200980137118Publ. N°: 102159285BGrantedExpiry: 17.07.2029

Appl. N°: 201280050382Publ. N°: 103889439AUnder examination

China, Hong Kong SAR

Appl. N°: 20130100580Publ. N°: 1173402A

Appl. N°: 20130100581Publ. N°: 1173403AStatus not available.

22


Patent 1 Patent 2 Patent 3 Patent 4Colombia Appl. N°: 20090042384

Publ. N°: 6180506AGrantedExpiry: 27.04.2029

Appl. N°: 20110005448Publ. N°: 6351757A2GrantedExpiry: 19.01.2031

Costa Rica 10776AStatus not available

2011-0089AStatus not available.

Croatia P2012-0866BP2014-0693BEP designated.

Dominican Republic

P2011-0023AStatus not available.

Ecuador Appl. N°: 2009SP09288Publ. N°: 099288AStatus not available

SP11010777AStatus not available.

Egypt 2009040576AStatus not available

2011010126AStatus not available.

El Salvador 2009003239AStatus not available

2011003813AStatus not available

Eurasian Patent Office*

Appl. N°: 20110070241Publ. N°: 019327B1Status not available.

European Patent Office*


2310095B2540349B2540350BGrantedExpiry: 17.07.2029



Guatemala 200900097AStatus not available

Honduras 2009000792AStatus not available

2011000209AStatus not available.

India 3304/DELNP/2009Under examination

328/DELNP/2011Under examination

2234/CHENP/2013Deemed withdrawn

Israel 198401AGrantedExpiry: 23.10.2027

210580AGrantedExpiry: 11.01.2031

Japan Appl. N°: 2009534619Publ. N°: 2010507661APatent N°: 5268927BGrantedExpiry: 23.10.2027

Appl. N°: 20110520110Publ. N°: 2011528713APatent N°: 4920797B2GrantedExpiry: 17.07.2029

Appl. N°: 2013531744Publ. N°: 2013544232AWithdrawn


Malaysia Appl. N°: 2011PI00310Publ. N°: 152070A

Mexico 2009004556AUnder examination




Morocco Appl. N°: 31877Publ. N°: 30893BStatus not available

Appl. N°: 33556Publ. N°: 32502B1Status not available

New Zealand Appl. N°: 20070576345Patent N°: 576345AGrantedExpiry: 23.10.2027

Appl. N°: 20090590638Patent N°: 590638AGrantedExpiry: 17.07.2029

23


Technical Report

Patent 1 Patent 2 Patent 3 Patent 4Norway 20092053L

Under examination

Pakistan+ 671/2009Under examination412/2012Granted (filed 26.06.2012)

Peru Appl. N°: 20110006720Publ. N°: 02122011AGrantedExpiry: 17.07.2029

Philippines 12009500765BGrantedExpiry: 21.04.2029

12011500151A

Republic of Korea

Appl. N°: 1020097010912Publ. N°: 1020090075874ARefused

Appl. N°: 1020117003982Publ. N°: 1020110036627APubl. N°: 10201313675BGrantedExpiry: 17.07.2029

Appl. N°: 1020137010752Publ. N°:1020130120469AUnexamined

Appl. N°: 1020147006888Publ. N°: 1020140059236AUnexamined

Russia Publ. N°: 2009120056APatent N°: 2468029CGrantedExpiry: 23.10.2027

Serbia Appl. N°: P-2012/0463Publ. N°: 52534BEquivalent to EP2310095

Appl. N°: P-2014/0375Publ. N°: 53420BEquivalent to EP2540350EP designated

South Africa 200902475ALapsed

Thailand+ 124148A(0901003251A)Under examination

Ukraine Appl. N°: 20090005267 Publ. N°: 95990C2Granted?Status not available

Appl. N°: a201102068Patent N°: 100436CGrantedExpiry: 17.07.2029

USA Appl. N°: 12/447,342Publ. N°: 20100099695AUnder examination

Appl. N°: 12/504,955Publ. N°: 20100029666APatent N°: 7973040B2

Appl. N°: 13/876,908Publ. N°: 20130280214AUnder examination


Appl. N°: 13/112,281Publ. N°: 2011/0224134APatent N°: 8080654B2Expiry: 17.07.2029

Viet Nam+ 1-2009-01058Under examination

1-2011-00289Under examination

24


Patent 5 Patent 6 Patent 7 Patent 8 Patent 9WO2013028471A1PCT/US2012/051182

WO2013028470A1PCT/US2012/051177

WO2013066753A1PCT/US2012/062145

WO2013101552A1PCT/US2012/070356

WO2013106631A1PCT/US2013/021118

Applicants Merck Sharp & Dohme (USA & UK)

Merck Sharp & Dohme (USA)

Merck Sharp & Dohme (USA)MSD Italia (IT)

AbbVie Inc. (USA) AbbVie Inc. (USA)

Filing date 16.08.2012 16.08.2012 26.10.2012 18.12.2012 11.01.2013

Title Methods and intermediates for preparing macrolactams.

Process and intermediates for preparing macrolactams.

Compositions useful for the treatment of viral diseases.

Methods for treating HCV.

Processes for making HCV protease inhibitors.

Subject matter Intermediates and processes for their preparation

Intermediates, processes for their preparation and processes for preparation of macrolactams (grazoprevir)

Compositions comprising grazoprevir with another HCV inhibitor other than elbasvir

Treatment regimen comprising AbbVie HCV NS5A inhibitor + another anti-HCV agent (e.g grazoprevir) with or without ribavirin but interferon-free

Processes for making HCV protease inhibitors precursors

Priority data US 61/525,462 – 19.08.2011US 61/533,439 – 12.09.2011US 61/533,915 – 13.09.2011US 61/539,540 – 27.09.2011

US 61/525,462 – 19.08.2011US 61/533,439 – 12.09.2011US 61/533,915 – 13.09.2011US 61/539,540 – 27.09.2011

US 61/553,677 – 31.10.2011

US 61/580,871 – 28.12.2011

US 61/585,280 – 11.01.2012

African Regional Intellectual Property Organization*

Argentina

Australia 2012299223A1Under examination


Brazil

Canada 2844388A1Under examination



China Appl. N°: 201280050361Publ. N°: 103874414AUnder examination



China, Hong Kong SAR

Colombia

Costa Rica

Dominican Republic

Ecuador

Egypt

El Salvador

25


Technical Report

Patent 5 Patent 6 Patent 7 Patent 8 Patent 9Eurasian Patent Office*

European Patent Office*






Guatemala

Honduras

Croatia

India

Israel

Japan Appl. N°: 2014526217Publ. N°: 2014521750AUnexamined



Malaysia

Mexico 2014001945AStatus not available



Morocco

New Zealand

Norway

Pakistan+

Peru

Philippines

Republic of Korea



Russia Appl. N°:2014122154

Serbia

South Africa

Thailand

Ukraine

USA Appl. N°: 14/239,391Publ. N°: 20140243519AUnder examination



Appl. N°: 13/718,167Publ. N°: 20130172240AAbandoned

Appl. N°: 13/739,174Publ. N°: 20130178630A1Under examination

Viet Nam

Notes: Cells in grey colour indicate that no patent or patent application has been found in the INPADOC database or – in the cases of Pakistan, Thailand and Viet Nam – during the check at the National Patent Office. This may mean that no patent application was filed, that the application has not been found (e.g. in the case of clerical error), or the application had not been published at the time of the search. Information in this Annex should therefore always been checked at the relevant patent office.

*African Regional Intellectual Property Organization (ARIPO): Botswana, Gambia, Ghana, Kenya, Lesotho, Liberia, Malawi, Mozambique, Namibia, Rwanda, São Tomé and Príncipe, Sierra Leone, Somalia, Sudan, Swaziland, Uganda, United Republic of Tanzania, Zambia, Zimbabwe.

26


* European Patent Office (EPO): designated contracting states: Austria, Belgium, Bulgaria, Switzerland, Cyprus, Czech Republic, Germany, Denmark, Estonia, Spain, Finland, France, United Kingdom, Greece, Hungary, Ireland, Iceland, Italy, Liechtenstein, Lithuania, Luxembourg, Latvia, Monaco, Malta, Netherlands, Poland, Portugal, Romania, Sweden, Slovenia, Slovakia, San Marino, Turkey; Extension states: Albania, Bosnia & Herzegovina, Croatia, Montenegro, Macedonia (former Yugoslav Republic of Macedonia), Serbia.

* Eurasian Patent Organization (EA): Armenia, Azerbaijan, Belarus, Kazakhstan, Kyrgyz Republic, Moldova, Russian

Federation, Tajikistan and Turkmenistan.

+ Confirmed in checks at the local patent office.

27

ANNEX 2. Process chemistry extracted from grazoprevir patents/applications

Technical Report


PATENT 1This patent/application discloses but does not claim processes for the preparation of the claimed com-pounds and their key intermediates.

By using the appropriate intermediates (numbered A1, B27 and C17 in the patent application), the com-pound of example 118 (which has a structure that is very similar to grazoprevir) was prepared according to the procedures of example 94 in the application.

v Intermediate A1

The process for the preparation of intermediate A1 is depicted below:

NH2 N

OS

H

OO

NH O

OHboc NS

H

HO O

+

A1 A'1 A"1

Intermediate A1 is prepared by coupling compound A’1 with compound A”1 according to the following scheme:

NO

OH

H

boc

NSH

H

OO

NH O

NH

Sboc

O O1. CDI, THF

2. , base

Intermediate A’1 can be prepared according to the process depicted below:

N

R

COOPPh halohalo

N

ROP

OPh

NH2

OP

OBocNH

OP

O

+ 1. MOtBu, toluene

2. TBME extract.3. aq. HCl

.HCl

(Boc)2O, base

racemate

(1:1) mixture of (1R,2S) & (1S,2R)

28


The racemate obtained is resolved by a stereoselective enzymatic process. In the presence of an enzyme, the undesired (1S,2R) enantiomer undergoes ester cleavage leading to the corresponding carboxylic acid while the desired (1R,2S) enantiomer does not undergo ester cleavage. Upon completion, the ester 5a is separated from the acid 6 by known methods.

The Boc protected ester is hydrolyzed into the corresponding acid, and the product obtained is then coupled with cyclopropyl sulfonamide according to the scheme below:

NO

OH

H

boc

NSH

H

OO

NH O

NH

Sboc

O O1. CDI, THF

2. , base

A'1

The cyclopropyl sulfonamide A”1 used can be prepared according to the process depicted below:

ClS Cl

OONH2 N

S

H

ClO O

NS

H

O O

NSH

H

O O

+

base

acid

A"1

v■ Intermediate B27

B27 B26

A process for the preparation of intermediate B27 is disclosed; however, intermediate B25 (B25a and B25b) would be the intermediates of use for the preparation of grazoprevir.

B25a and B25b

Similarly to the process for the preparation of intermediate B27 described in the above-mentioned patent application, intermediates B25a & B25b useful for the preparation of grazoprevir can be prepared accord-ing to the following scheme:

29


Technical Report

MgBr OSiMe3

OSiMe3OSiMe3

OSiMe3 OH

OHO

O

NO

O N

O

H

O

O

O N

O

H

O

O

1. Cu(I)Br.SMe2, HMPA, THF

2. acrolein, TMSCl, THF3. TEA, hexane

Et2Zn.Toluene , CH2I2, hexane

TBAF, THF

+DMAP, PhMe

v■ Intermediate C17

Intermediate C17 can be prepared according to the process depicted below:

O

O

O

NH2

NH2ONboc O

OO

SOO

Br

N

NN

O

O

boc

O O

N

NN

O

O

H

O O

+ +

1231 2 3

1. compound 1 + compound 2 in EtOH2. product of step 1, compound 3, Cs2CO3, NMP

HCl, dioxane

HCl

30


Finally, grazoprevir could be prepared following the process depicted in the scheme below:

N

NN

O

O

H

OO

O N

O

H O

O

BF3.K

NN

O

O

N

O

NH O

NH

SO O

O

NHO

O

+

C171. DIPEA, HATU, DMF

2. a) TEA, EtOH

b) Pd(dppf).DCM

3. Zhan catalyst, DCE

4. Pd/C, H2, MeOH CELITE

5. LiOH.H2O IN (H2O:THF)

6. DIPEA, DMAP, TBTU INTERMEDIATE A1 in DCM

31


Technical Report

PATENT 2The patent discloses, without claiming them, processes for making grazoprevir, including processes for making the key intermediates. These processes are summarized below.

The processes may represent opportunities to make grazoprevir while avoiding the later patented pro-cesses (though the latter may be more efficient).

Synthesis of intermediatesv■ Intermediates A

The process for the preparation of intermediate A1 has been detailed earlier in the section on intermedi-ates for compounds (I) of WO2008057209 (patent 1). Please refer to that section.

v■ Intermediate B1: 3-methyl-N-({[(1R,2R)-2-pent-4-en-1-yl cyclopropyl]oxy}carbonyl)-L-valine

B1

The process for the preparation of intermediate B1 is depicted below.

MgBr OSiMe3

OSiMe3OSiMe3

OSiMe3 OH

OHO

O

NO

O N

O

H

O

O

O N

O

H

O

O

1. Cu(I)Br.SMe2, HMPA, THF

2. acrolein, TMSCl, THF3. TEA, hexane

Et2Zn.Toluene , CH2I2, hexane

TBAF, THF

+DMAP, PhMe

The (1R,2R) enantiomer was separated from the (1S,2S) enantiomer by flash chromatography.

32


v■ Intermediates C1: methyl (4R)-[(3-chloro-7-methoxyquinoxalin-2-yl)oxy]-L-prolinate HCl.

C1

The process for the preparation of intermediate C1 is depicted in the scheme below.

NH2

NH2O

O

OO

O

NN

O

OHOH

NN

O

ClOH

NN

O

ClOH

NO

O

O O

OSO O

Br

NO

O

O O

O

NN

Cl

O

NO

O

H

O

NN

Cl

O

HCl

HCl Et3N

1. SOCl2 (1eq.), DMF

2. HCl, H2O:Et2O

+ Cs2CO3, NMP

4N HCl in dioxane, DCM

HCl

Example 1: Potassium {[(1R,2S)-1-( { [(1aR,5S,8S.10R,22aR)-5-tert-butyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxalin-8-yl]carbonyl}amino)-2-vinylcyclopropyl]carbonyl}(cyclopropylsulfonvl)azanide

33


Technical Report

The process for the preparation of grazoprevir potassium salt is given in the scheme below.

N

NN

ClO

H O

O

O

O N

O

H

OH

O

N

NN

ClO

O

O

O

ONH

O

O

BFF

F

N

NN

O

O

O

O

ONH

O

O

NO

O

NN

O

O

ONH

O O

NO

O

NN

O

O

ONH

O O

NO

OH

NN

O

O

ONH

O O

+DIEA, HATU, DMF

_K+ Et3N, EtOH

Zhan-1 catalyst

DCE

H2, Pd/C MeOH/dioxane

LiOH.H2O

H2O/THF

NO

OH

NN

O

O

ONH

O O

N

ONH2

H

SO O

NO

N

NN

O

O

ONH

O O

H

N

O

H

SO O

NO

N

NN

O

O

ONH

O O

H

N

O

H

SO O

+

DIEA, DMAP, TBTU DCM

tBuOK, EtOH

34


PATENT 5 Overall processes for producing grazoprevir and several key intermediates are depicted below.

v■ The process for the preparation of intermediate compound 8

v■ ■The process for the production of quinoloxine compound 11 and its coupling with hydroxyproline compound 12 to produce compound 13

35


Technical Report

v■ Process for the preparation of compound A (grazoprevir)

36


PATENT 6 Processes for producing grazoprevir and key intermediates disclosed and claimed is depicted below.

Overall synthetic scheme

Prefered overall scheme

The application claims compounds of general formula (I) – in particular compounds 14, 16, 16A and 17 or salt thereof; and a method of making compounds 16A, 16 and 17. It also claims a method for making compounds 18 and 14, and a method for making compound A (grazoprevir).

37


Technical Report

Preparation of compound A (grazoprevir)

Preparation of compound A (grazoprevir) – alternative procedure

Processes for the preparation of compounds 3, 4, rac-5, rac-6, 7, 8, 10 and 11 are as disclosed in WO2013028471 (patent 5).

Finally, it claims an MeCN solvate of a compound 14 methylsulfonic acid salt where the solvate is char-acterized by an X-ray powder diffraction pattern obtained using copper Kα radiation, and a compound 19 hydrate-I characterized either by an X-ray diffraction pattern obtained using copper Kα radiation or by a solid-state carbon-13 CPMAS NMR spectrum.

38


PATENT 9 This application discloses and claims processes that permit the incorporation of the moiety below, or an equivalent one, into precursors of HCV protease inhibitors.

In one aspect, the processes comprises reacting compound I with compound II to form compound III; and further reacting compound III with R3-OH to form compound IV.

I II III IV

I’ II’ III’ IV’

The application also discloses processes for making compound II, as depicted in the scheme below:

+ g g

Finally, the application claims compounds of general formula, as depicted below:

39


Technical Report

Illustrative example:

Review of the Grazoprevir Patent Landscapeunitaid.org/assets/Grazoprevir_Patent_Landscape.pdf ·...

Documents

Transcript of Review of the Grazoprevir Patent Landscapeunitaid.org/assets/Grazoprevir_Patent_Landscape.pdf ·...